An
incretin hormone,
glucagon-like peptide-1 (GLP-1), has been shown to lower plasma
glucose via
glucose-dependent insulin secretion and to reduce appetite. We previously found that the
biguanide metformin, an
antidiabetic agent, causes a significant increase of plasma active
GLP-1 level in the presence of
dipeptidyl peptidase IV (DPPIV) inhibitor in normal rats. This finding suggested that the combination treatment might produce a greater
antidiabetic and
anorectic effect, based on enhanced
GLP-1 action. In this study, we assessed the effects of subchronic treatment with
metformin and a DPPIV inhibitor,
valine-pyrrolidide (val-pyr), on
glycemic control, food intake, and
weight gain using Zucker fa/fa rats, a model of
obesity and
impaired glucose tolerance. The combination treatment caused a significant increase of
GLP-1 level in Zucker fa/fa rats. In a subchronic study, val-pyr,
metformin, or both compounds were administered orally b.i.d. for 14 days. The combination treatment significantly decreased food intake and
body weight gain, although neither
metformin nor val-pyr treatment alone had any effect. In an oral
glucose tolerance test on day 1, the coadministration caused a greater improvement of
glucose tolerance and a prominent increase of plasma active
GLP-1 without marked insulin secretion. The 14-day combination treatment produced a potent reduction of fasting
blood glucose and plasma
insulin levels. These results demonstrate that the combination
therapy of
metformin with DPPIV inhibitor leads to reduced food intake and
body weight gain, most likely through the significant increase of plasma
GLP-1 level. The combination
therapy seems to be a good candidate for treatment of
type 2 diabetes with
obesity.